PROJECT SUMMARY: At least one-third of stroke survivors suffer from post-stroke depression (PSD), which has been shown to negatively affect prognosis. Although PSD after ischemic stroke has been studied, very little is known about the frequency and severity of depression or depressed mood associated with intracerebral hemorrhage (ICH). However, patients who experience ICH do develop PSD. Identifying new drug targets for PSD specific for ICH patients is a pressing need because antidepressants, particularly selective serotonin reuptake inhibitors, are associated with an elevated risk of bleeding, increased stroke severity, and increased mortality from stroke or ICH. In an effort to limit ICH injury and improve functional recovery, we have investigated PSD in preclinical ICH models and shown for the first time that the mouse cortical ICH model produces depression-like behavior. Clinically, however, ICH occurs most commonly in the basal ganglia, an area that contributes to the development of PSD. Indeed, our pilot data showed that striatal ICH does lead to depression-like behavior in mice. The pathogenesis of PSD is complex, but a heightened inflammatory response and increased reactive oxygen species (ROS) production might be two key biochemical factors. The transcription factor Nrf2 is a master regulator of ROS and inflammation. Enhancing this endogenous system might provide a mechanism to reduce PSD after ICH. We have reported that Nrf2 activity is neuroprotective after ICH. We have also shown that the exacerbation of brain injury in Nrf2 knockout mice is associated with increased inflammation and ROS production and that the brain-permeable, Nrf2 inducer (?)-epicatechin offers neuroprotection against ICH. Brain-derived neurotrophic factor (BDNF) is one of the Nrf2 target genes, and Nrf2/BDNF signaling was shown to be involved in the antidepressant-like effect produced by agmatine and fluoxetine. Because the neurobiologic mechanisms of PSD may differ from those of other depression subtypes, it is unknown whether deletion/activation of Nrf2 exacerbates/mitigates PSD after striatal ICH. The overall objective of this R21 is to investigate whether the striatal ICH model can be used to investigate PSD after ICH, and if so, to determine the role of the Nrf2/BDNF pathway in the pathogenesis of PSD. In two specific aims, we will test the hypothesis that dysregulation of the Nrf2/BDNF pathway contributes to the development of PSD after ICH. Aim 1 will determine whether striatal ICH produces PSD in young mice of both sexes, and Aim 2 will determine whether dysregulation of the Nrf2 pathway contributes to PSD after ICH. Successful validation of the striatal ICH model as an appropriate approach to investigate PSD will provide the rationale for expanded preclinical studies on PSD. This project is highly clinically relevant and represents the first preclinical evaluation of PSD in a striatal ICH model. The results will provide insight into the molecular mechanisms of PSD after ICH and will identify and validate new therapeutic targets for ICH-induced PSD, an under-investigated clinical problem identified by the American Heart Association (Stroke 2017; 48: e30-e43).